Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) which occurs at young adults, more prevalent in women than in men. The etiology of MS is unknown, but it is thought to result from a combination of genetic and environmental factors. MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other and control body functions. The clinical disability is linked to an inflammation of the myelin, the protective sheath around the axons of the central nervous system (CNS), which is damaged due to an autoimmune attack and neurodegenerative processes. As a consequence, the white matter of the brain and spinal cord becomes scarred by focal lesions (plaques) leading to progressive neurological dysfunction including demyelination and neurodegeneration.
Currently, there is no specific test for diagnosing MS and the diagnosis relies on the recognition of the clinical history of the subject. Clinical data which includes various episodes of neurologic symptoms, especially in young adults, suggests the diagnosis of MS. In many instances the diagnosis can be supported by the analysis of the cerebrospinal fluid (CSF) and evoked potential (EP) studies of the visual, auditory and somatosensory pathway, as well as by recently applied techniques of Magnetic Resonance Imaging (MRI) of the brain and spinal cord. These techniques, however, suffer from several disadvantages. For example, the analysis of the CSF is performed by electrophoresis for detecting oligoclonal bands (OCB) of IgG, which is a biomarker present in 75-85% of individuals having MS and can provide evidence of chronic inflammation of the central nervous system (Link et al., J. Neuroimmunol., 180(1-2), 17-28, 2006). However, OCB are often non-detectable at the early stages of MS thereby leading to false negative results. The extraction of the cerebrospinal fluid involves an invasive lumbar puncture procedure that can cause a major discomfort to the subject with accompanying symptoms including dizziness, severe headache, etc. MRI is an expensive procedure which requires the injection of a contrast material (gadolinium) prior to performing the scan. Additionally, MRI cannot provide information about the pathological composition of the lesions.
Multiple sclerosis may progress and regress unpredictably. However, there are several patterns of symptoms. Approximately 85-90% of patients experience a relapsing-remitting (RRMS) course at the initial stage which then becomes progressive (PMS) in 40% of the patients. Progressive MS can be sub-classified into primary progressive course (PPMS) and secondary progressive course (SPMS). The different MS subtypes are characterized by the past course of the disease (e.g. unpredictable relapses, remissions and progression of neurologic decline). From a clinical perspective, patients with different disease courses show different responses to treatment. For instance, patients with RRMS are more likely to respond to immunomodulatory therapy than those with a progressive disease course (Bitsch et al., CNS Drugs, 16(6), 405-418, 2002). Thus, characterizing the MS subtype is important not only for prognosis but also for disease management. Moreover, early detection of MS is extremely important to allow early onset of treatment that could significantly slow down the progression of the disease and related accumulating disability as well as improve health-related quality of life.
Biomarkers are anatomic, physiologic, biochemical or molecular parameters associated with specific disease states. The search for MS biomarkers has been focused on indicators of the general activity of the inflammatory process as well as its consequences such us neurodegeneration and axonal loss. Several biomarkers and methods of use thereof in diagnosing MS are disclosed in e.g. WO 2010/113096, WO 2007/041245, and WO 2005/027733. However, most of the MS biomarkers are CSF or serum derived thus necessitating the performance of invasive tests, which limit the possibilities of repeated measurements as part of long-term follow-up, as required in these chronic patients.
WO 2004/065404 discloses a method for detecting a target analyte/biomarker in exhaled breath comprising a) exposing to the exhaled breath an aptamer capable of selectively binding to the target analyte/biomarker, wherein the aptamer is linked with a molecular beacon; and b) detecting a signal generated by the molecular beacon.
WO 2007/086986 discloses a method for detecting a target analyte/biomarker in exhaled breath comprising: a) exposing to the exhaled breath a molecular recognition agent capable of selectively binding to the target analyte/biomarker, wherein the molecular recognition agent is linked with a signaling agent; and b) detecting a signal generated by the signaling agent.
WO 2004/065404 and WO 2007/086986 further disclose a method for screening analytes/biomarkers which method includes providing blood specimens from patients with known diseases (i.e., Alzheimer's disease, multiple sclerosis) and screening the specimens for the presence of biomarkers in blood components and exhaled breath.
WO 2004/090534 discloses a non-invasive breath analysis using Field Asymmetric Ion Mobility Spectrometry (FAIM) for the detection of several disorders. Specifically, FAIM spectrometers are suggested as being useful for analyzing the presence of pentane in a patient sample, for example a breath sample, which provides a marker for arthritis and multiple sclerosis.
WO 2009/144725 to one of the inventors of the present application discloses a system for detecting volatile organic compounds derived from a breath sample, the system comprising: (a) an apparatus comprising an array of chemically sensitive sensors of single walled carbon nanotubes coated with non-polar small organic molecules, and (b) a processing unit comprising a learning and pattern recognition analyzer wherein the learning and pattern recognition analyzer receives sensor output signals and compares them to stored data.
WO 2010/064239 to one of the inventors of the present application discloses a system comprising an array of sensors for measuring volatile organic compounds as biomarkers for diagnosis, prognosis and monitoring of renal insufficiencies, the system comprises an array of sensors comprising a (semi-) conductive random network of single-walled carbon nanotubes (SWCNTs) coated with an organic coating which comprises oligomers or polymers modified with at least one polar functional group, in conjunction with learning and pattern recognition algorithms.
WO 2009/066293 to one of the inventors of the present application discloses an apparatus comprising at least one chemically sensitive sensor for detecting volatile and non-volatile compounds, wherein the chemically sensitive sensor comprises cubic nanoparticle conductive cores capped with an organic coating. Methods of use thereof in identifying various disease biomarkers, and in food quality and environmental control are disclosed.
WO 2010/079490 to one of the inventors of the present application discloses a sensor array for detecting biomarkers for cancer in breath samples. The sensor array is based on 2D films or 3D assemblies of conductive nanoparticles capped with an organic coating wherein the nanoparticles are characterized by a narrow size distribution.
There remains an unmet need for a non-invasive and cost-effective technique for confirming the diagnosis of Multiple Sclerosis, distinguishing the disease specific subtypes (relapsing-remitting vs. progressive Multiple Sclerosis), assessment of disease activity (predicting relapse vs. remission) and prognosis as well as the assessment and prediction of response to therapeutics in patients with MS.